Corneal epithelial cells have acquired the ability to rapidly change their cell:cell and cell:substrate adhesion junctions to permit mobilization after injury. Integrins on the epithelial cells are used as signaling and cell:substrate adhesion molecules and laminins and collagens in the basement membrane and stroma act as substrates to support metaloproteinase-dependent cell migration. The signaling and adhesive functions of integrins can be regulated by their lateral association with other integral membrane molecules including proteoglycans of the syndecan family. Data show that a mouse strain genetically deficient in syndecan-1 exhibits delayed corneal and skin wound healing due in part to slower epithelial cell migration. We hypothesize that the activity of integrins in epithelial cells is regulated in part by syndecan:integrin associations and that the loss of syndecan-1 in epithelia results in a reduction in cell signaling via integrins and growth factor receptors. The following specific aims are proposed to further our understanding of the molecules regulating reepithelialization in the cornea: Aim 1. To determine the roles played by cell proliferation, differentiation and protein synthetic rates in the impaired wound response observed in the syndecan-1 knock-out (synd1ko) mouse in vivo. Aim 2. To determine if it is possible to restore the normal phenotype to synd1ko corneal cpithelial cells by providing exogenous synd1 and/or growth factors that stimulate the EGF-receptor. and Aim 3. To determine in cultured epidermal keratinocytes derived from the syn1ko mouse and in mouse and human corneal epithelial cell lines, the roles played by synd1-mediated signaling in regulating cell proliferation, apoptosis, cell adhesion, and endocytosis. By examining the mechanism of delayed corneal wound healing in genetically engineered mice, basic concepts regulating healing will be revealed and better treatments for those suffering from poor healing can be developed.